Paclitaxel (Taxol®) is a therapeutic agent with antitumor activity against ovarian, breast, and lung carcinomas. The compound is extracted from the bark of the Pacific yew tree Taxus brevifolia, as well as from needles and stems of this and other Taxus species, and its complex chemical structure has been determined. Interest in this compound arises from not only its clinical activity against poorly responsive solid tumors but also from its unique mechanism of action. Paclitaxel promotes tubulin polymerization and stabilizes microtubules that result in the inhibition of cell migration and chromosome segregation by blocking the transit of cycling cells in the G2/M phase. More recently, paclitaxel has been proposed as a therapeutic for stabilizing microbules in the brain cells of individuals who are deficient in normal tau proteins, for example in individuals suffering from Alzheimer's Disease. See Trojanowski et al., U.S. Pat. No. 5,580,898.
In 1997, a group of Japanese researchers described a novel small synthetic compound designated GS-164, which was reported to stimulate tubulin polymerization and stabilize microtubules. See Shintani et al., GS-164, a small synthetic compound, stimulates tubulin polymerization by a similar mechanism to that of Taxol, Cancer Chemother Pharmacol 40:513-520 (1997); Japanese Patent No. 8-325147 (1996). The researchers reported that GS-164 has activities similar to those of paclitaxel in vitro and in vivo, even thought it was structurally unrelated. The compound was reported to stimulate tubulin polymerization with one-tenth the activity of paclitaxel. According to the authors, the stereoisomer of GS-164 that was responsible for its microtubule-stablizing effects was determined to be the R/R isomer, which mimicked the structure of paclitaxel.
